Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to non-suppurative inflammatory destruction of small intrahepatic bile ducts. Because some other autoimmune diseases appear to respond favorably to certain immunosuppressive agents, trials of selected immunosuppressive drugs are being undertaken in patients with PBC. One promising drug of this type is methotrexate. Ten patients with symptomatic PBC were admitted to an open trial of low-dose (15 mg) once weekly oral methotrexate. Two patients with advanced (stage III-IV) disease dropped out after 4-5 months. The remaining 8 have been followed for up to 36 months. Methotrexate therapy in these patients was associated with significant decreases in elevated serum levels of IgM and alkaline phosphatase and a more than 50% decrease in symptom scores for fatigue and pruritus. Serum ALT levels initially increased (at 4 and 8 mo.) but the mean subsequently fell to 10% below baseline. In 8 patients, who had liver biopsies before and after one year of treatment, methotrexate was associated with a substantial decrease in hepatic inflammation but no obvious change in fibrosis. Patients with Stage III disease progressed during the second year of treatment and methotrexate was discontinued in 3 of these patients. A randomized trial of two doses of methotrexate (7.5 and 15 mg/week) for asymptomatic as well as symptomatic patients with PBC has been initiated. 25 patients have been admitted to this trial.